Non-melanoma skin cancer is by far the most common neoplasm in the United States. Although morbidity in these patients is relatively low due to early detection and ease of tumor excision, the study of skin cancer can reveal mechanisms of tumor initiation and progression that are relevant to many different tumor types. An important subset of skin cancer patients, those who have undergone kidney transplantation, develop multiple skin tumors, many of which show characteristics of advanced, invasive lesions. These are difficult to treat, can be very disfiguring, and are a significant cause of morbidity. Although all transplant patients are treated with immunosuppressant drugs, in particular cyclosporine, only a subset of the treated patients actually develops invasive skin cancer. This project will investigate the possibility that some individuals are genetically predisposed to the development of multiple skin cancers after treatment with immunosuppressant drugs. In particular, recent evidence that the major immunosuppressant drug used, cyclosporine, acts at least in part through the TGFI3 pathway, suggests that polymorphisms in this signaling pathway may confer increased risk of invasive skin cancer development. We will test polymorphisms in the TGFI31 gene, and in other genes, that are known to affect their biological activities in tumor progression or angiogenesis. Evidence from mouse models further supports an important role for TGFI3 signaling in tumor progression. We will exploit the power of mouse genetics as an unbiased approach to the identification of low penetrance tumor susceptibility genes that does not depend on prior knowledge of candidates within the TGFI3 signaling pathway. This combined mouse-human genetic strategy for the identification of susceptibility genes will ultimately provide screening tools for assessment of risk of tumor development in transplant patients that have undergone long term CsA treatment, as well as providing targets for prophylactic drug development for these patients.